Insulin-dependent Type 1 diabetes (T1D), also known as Juvenile Diabetes or Insulin-Dependent Diabetes Mellitus, is a devastating autoimmune disease that destroys beta cells within the pancreatic islets and afflicts over 10 million people worldwide. Their autoimmune process is known to lead to hyperlipidemia and accelerated atherosclerosis. These patients face life-long risks for blindness, cardiovascular and renal diseases, and complications of insulin treatment. Increasing evidence regarding the pathomechanism of T1D indicates that islets are destroyed by the relentless attack by autoreactive immune cells evolving from an aberrant action of the innate, in addition to adaptive, immune system that produces islet-toxic cytokines, chemokines, and other effectors of islet inflammation.
T1D results from the progressive destruction of insulin-producing beta cells in pancreatic islets caused by pro-inflammatory and pro-apoptotic effectors of innate and adaptive immunity. Extraordinary advances with insulin monotherapy and understanding of the critical role of the adaptive immune system in the T1D pathomechanism have not translated to diabetes reversal. Patients remain at risk for the serious complications inherent to the autoimmune and metabolic derangements in T1D. Patients with end-stage diabetic nephropathy can receive simultaneous kidney-pancreas (SPK) transplants. Secondly, T1D patients who developed end-stage diabetic nephropathy and received a successful kidney transplant are potentially eligible for pancreas-after-kidney (PAK) transplantation. Thirdly, T1D patients with normal renal function albeit with difficult to control insulin therapy can be treated with pancreas transplant alone (PTA). These approaches have a limited success rates although the positive outcome of SPK and PAK transplants includes decreasing or reversing diabetic neuropathy (Jamiolkowski R M et al. Yale Journal of Biology and Medicine 85 (2012), pp. 37-43). Islet transplantation poses less risk than major organ transplant surgery. However, the risk of immune rejection remains similar. The currently used Edmonton protocol for islet transplantation is continually improving by using the portal vein and liver for implantation of isolated islets. Better preservation of isolated islets before and after transplantation continues to be a challenge that can be met by new treatment that protects transplanted beta cells from autoimmune attack.
Given the side effects of insulin therapy and current immunosuppressive regimens, the search for new therapeutic approaches continues. The requisite roles of islet-specific autoreactive T and B cells have been well established and have been the primary target of current clinical investigations. Building on the role of adaptive immunity, both T cell-directed immunotherapy with anti-CD3 and the B cell-directed action of rituximab (anti-CD20) have shown similar efficacy in delaying the progression of new-onset diabetes. Unfortunately, while clinical benefit to patients in these trials has been recorded (Herold et al. (2005) Diabetes 54: 1763-1769), insulin-secreting capacity continues to decline in treated individuals and these regimens have not restored stable tolerance to islet tissue, perhaps because they do not completely target the islet-destructive autoimmune inflammatory process. New therapies that protect islets from autoimmune destruction and allow continuing insulin production are needed.